Ma Yufei, Zhang Xu, Tang Shaoxin, Xue Li, Wang Jing, Zhang Xiaohui
Bioinspired Engineering and Biomechanics Center (BEBC), The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China.
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Center for Mitochondrial Biology and Medicine, School of Life Science and Technology, International Joint Laboratory for Micro/Nano Manufacturing and Measurement Technology, Xi'an Key Laboratory for Biomedical Testing and High-End Equipment, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China.
APL Bioeng. 2023 Feb 22;7(1):016110. doi: 10.1063/5.0124424. eCollection 2023 Mar.
Dynamic extracellular matrix (ECM) mechanics plays a crucial role in tissue development and disease progression through regulation of stem cell behavior, differentiation, and fate determination. Periodontitis is a typical case characterized by decreased ECM stiffness within diseased periodontal tissues as well as with irreversible loss of osteogenesis capacity of periodontal tissue-derived human periodontal tissue-derived MSCs (hMSCs) even returning back to a physiological mechanical microenvironment. We hypothesized that the hMSCs extendedly residing in the soft ECM of diseased periodontal tissues may memorize the mechanical information and have further effect on ultimate cell fate besides the current mechanical microenvironment. Using a soft priming and subsequent stiff culture system based on collagen-modified polydimethylsiloxane substrates, we were able to discover that extended preconditioning on soft matrices (e.g., 7 days of exposure) led to approximately one-third decrease in cell spreading, two-third decrease in osteogenic markers (e.g., RUNX2 and OPN) of hMSCs, and one-thirteenth decrease in the production of mineralized nodules. The significant loss of osteogenic ability may attribute to the long-term residing of hMSCs in diseased periodontal tissue featured with reduced stiffness. This is associated with the regulation of transcriptional activity through alterations of subcellular localization of yes-associated protein and nuclear feature-mediated chromatin organization. Collectively, we reconstructed phenomena of irreversible loss of hMSC osteogenesis capacity in diseased periodontal tissues in our system and revealed the critical effect of preconditioning duration on soft matrices as well as the potential mechanisms in determining ultimate hMSC fate.
动态细胞外基质（ECM）力学通过调节干细胞行为、分化和命运决定，在组织发育和疾病进展中发挥关键作用。牙周炎就是一个典型例子，其特征是患病牙周组织内的ECM硬度降低，以及牙周组织来源的人牙周组织间充质干细胞（hMSCs）的成骨能力不可逆丧失，即便回到生理力学微环境也是如此。我们推测，长期存在于患病牙周组织柔软ECM中的hMSCs可能会记住力学信息，并除了当前的力学微环境外，对最终的细胞命运产生进一步影响。使用基于胶原蛋白修饰聚二甲基硅氧烷底物的软预处理及随后的硬培养系统，我们发现，在软基质上进行长时间预处理（例如暴露7天）会导致细胞铺展减少约三分之一，hMSCs的成骨标志物（例如RUNX2和OPN）减少三分之二，矿化结节产生减少十三分之一。成骨能力的显著丧失可能归因于hMSCs长期存在于硬度降低的患病牙周组织中。这与通过Yes相关蛋白的亚细胞定位改变和核特征介导的染色质组织改变来调节转录活性有关。总体而言，我们在系统中重现了患病牙周组织中hMSC成骨能力不可逆丧失的现象，并揭示了在软基质上预处理持续时间的关键作用以及决定hMSC最终命运的潜在机制。
